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Monday, May 14, 2012

“I'll never understand what
possessed my mother to put her faith in God's hands, rather than her local
geneticist” - Vincent, the protagonist in the
classic sci-fi flick GATTACA.

I had the pleasure of rewatching
this film recently and offering some commentary on the scientific ideas it
centres on at an event organised by Newstalk radio’s Futureproof program at Dublin’s
Science Gallery.It was a very
enjoyable evening, with a lively crowd and some thought-provoking
questions.I had forgotten what a
great film it is, and remarkably prescient in its vision of the possible future
applications of genetic technologies.

Though released in 1997, when the
Human Genome Project had only just begun, it imagines a world where access to
everyone’s complete genetic information is routine, where most people are
conceived in vitro and embryos are prescreened for all manner of perceived
genetic defects, and where those remaining few who were conceived the
old-fashioned way (with all the genetic baggage that comes along with that
method) are actively discriminated against.

It is especially timely to
consider these ideas, as cheap and routine whole-genome sequencing looks set to
become a reality.This is already
changing genetic research, leading to unprecedented breakthroughs in the
genetics of conditions like autism, for example, and also fundamentally
altering our conception of the spectrum of genetic variation in human
populations.But as more and more
people have their genomes sequenced, serious questions arise as to what we will
do with all that new information.

One consequence of routine
sequencing is that individuals may find out they are carriers for a number of
genetic conditions.We all carry
hundreds of potentially deleterious mutations, some of which are known to cause
disease, though often only if both inherited copies of the gene are
mutated.For very rare mutations,
this will not be a major issue as the chance that one’s spouse will also carry
it is vanishingly small (so potential offspring should never be affected).But many populations have certain
disease mutations segregating at quite high frequencies, due to population
founder effects, balancing selection or genetic drift.In Ireland, a particular mutation
causing cystic fibrosis (the “deltaF508” mutation) is at very high frequency
(as one of my parent’s carries it, I have a fifty percent chance myself).The carrier rate in the Irish
population for this and a number of other specific mutations is 1/19.There are many other examples of high-frequency
mutations causing a range of diseases in other populations – sickle-cell anemia
in Africans, beta-thalassemia in Cyprus, Tay-Sachs disease in Ashkenazi
Jews.

If you and your spouse know that
you are both carriers of such a mutation, then in vitro fertilisation with
preimplantation genetic diagnosis (PGD) becomes an attractive scenario.This is the method portrayed in
GATTACA, though taken to the nth degree, by screening against vast numbers of
mutations at once.In the present,
the technique is used to diagnose inheritance of usually just one, very
specific mutation, where one or both parents are known to be carriers.The diseases listed above are all
commonly tested for – others include mutations causing Huntington’s disease,
breast cancer, or other later-onset conditions.

With this technique, multiple
embryos are generated by in vitro fertilisation and allowed to develop for
several days.A single cell is
carefully removed from each and the DNA extracted.This can then be molecularly analysed to determine which
embryos have inherited the mutations causing concern.It is then possible to choose an embryo or embryos that have
not inherited the mutation and implant those.The remainder are usually discarded.

To many, this smacks of playing
God.To others, it is common sense
– if a couple can choose to have a healthy child versus one with a serious
disease, then why shouldn’t they?This
is summed up by this exchange from the film:

Antonio: We were just wondering if, if it is
good to just leave a few things to, to chance?

Geneticist: You want to give your child the best
possible start. Believe me, we have enough imperfection built in already. Your
child doesn't need any more additional burdens. Keep in mind, this child is
still you. Simply, the best, of you. You could conceive naturally a thousand
times and never get such a result.

The choice being made is to
implant one embryo over another.IVF
clinics do this routinely anyway, by “grading” embryos based on those which
look most likely to lead to a successful pregnancy (based on a number of
embryological criteria).This
choice does remind me, though, of the “Wasn’t” in this poem (Happy Birthday to
You) by Dr. Seuss:

"If we didn’t have birthdays, you wouldn’t be
you.

If you’d never been born, well then what would you do?

If you’d never been born, well then what would you be?

You might be a fish! Or a toad in a tree!

You might be a doorknob! Or three baked potatoes!

You might be a bag full of hard green tomatoes.

Or worse than all that…

Why, you might be a WASN’T!

A Wasn’t has no fun at all. No, he doesn’t.

A Wasn’t just isn’t. He just isn’t present.

But you…You ARE YOU!

And, now isn’t that pleasant!"

The other main application of
preimplantation genetic testing is to screen against possible chromosomal
anomalies (or aneuploidies), such as trisomy 21, which causes Down syndrome or
other abnormalities in the genetic complement.This is typically done with older women, where the chances
of such anomalies arising is increased, or in couples that have had several
miscarriages, which can also result from aneuploidies.

The prospect of routine
whole-genome sequencing adds another angle to this kind of preimplantation
screening and diagnosis, providing the means to select prospectively against
embryos with any potentially harmful mutations (whether carried by the parents
or new ones that have arisen in the egg or sperm).This starts to get closer to the scenario portrayed in
GATTACA, and raises the ethical question of which kinds of conditions or
genetic traits this procedure should be used for.

Currently, some countries (the
UK, Canada and Germany, for example) have laws limiting its use to screening
for serious genetic conditions.Others are more loose, however.In many American states it is legal to screen and select on the basis of
sex, for non-medical reasons.In
fact, a 2006 study (see below) found that 9% of PGD procedures carried out in IVF clinics in
the U.S. were performed for this reason.Other reasons include screening for an embryo with the same immune type
(“HLA type”) as a current child who is ill and requires a transplant of some
sort.Screening for these “savior siblings” was done in 1% of PGD procedures.And 3% used it for a reason I personally find jarring – to
specifically select embryos with a mutation causing a genetic condition.This is usually in cases where both
parents have either deafness or dwarfism and they want their child to be
similarly affected.This gets into
the political movement objecting to society labelling conditions as
“disabilities”.I can sympathise
with that to some degree – more for some conditions than others – but I think,
if it were my child, I would still rather he or she could hear.

In any case, these applications
illustrate the range of possibilities that will arise as we get routine access
to the entire genomes of prospective parents and of embryos generated in
vitro.Genetic testing can also
obviously be done post-implantation, of a fetus in utero.For example, screening by amniocentesis
for conditions like Down syndrome is routine, and in some countries, the
majority of such diagnoses result in the decision to terminate the pregnancy. Remarkably, it is now possible to screen a fetus’ DNA without the invasive procedure of amniocentesis, by sequencing the
entire fetal genome from DNA that enters the maternal bloodstream from dying
placental cells. (Independently sequencing the mother’s genome provides a
reference to distinguish fetal from maternal DNA).

Once genome sequencing becomes both
cheap and fast (as recent announcements of new technologies suggest may happen
very soon), it will change the game when it comes to these reproductive
technologies.Not only will we all
have more knowledge of mutations we may carry and wish not to pass on, we will
also have greater access to the complete DNA information of embryos or fetuses.Different societies will have to decide
what level of intervention they deem permissible.

The prospect envisioned in
GATTACA is not just that individual embryos are routinely prescreened and
selected, but that that process has led over time to the progressive weeding
out of mutations in the gene pool.This is the grand vision of eugenics realised through molecular
technology and not just selective breeding.Should we be concerned that this might become a reality?Will this kind of selection change gene
frequencies in specific populations?Would that be a bad thing?

In fact, this is already
happening.A program has been in
place in Cyprus since the 1970s where all prospective couples must be
genetically tested for the mutation causing beta-thalassemia (a serious and life-threatening
disease).Remarkably, the Greek
Orthodox Church is one of the strongest supporters of this program and will not
marry coupes who have not had the test.This has led many couples who find they are both carriers to not get
married, decide not to have children or decide to prescreen, either in vitro or
in utero, to detect the inheritance of two copies of the mutation, permitting
embryo selection or termination of a pregnancy.Collectively, these actions have led the rate of live births
affected by beta-thalassemia to decrease from 1/158 to effectively zero.On the one hand, the “eradication” of
the disease can be seen as a good thing.On the other, the selective termination of pregnancies of individuals
who will inherit what is now a more treatable disease than in previous years
may be troubling to many.

This is, in a sense, the ultimate
form of genetic discrimination.I
am not arguing against this program, not saying that it should not happen and
not saying I would not avail of these technologies in that situation
myself.Where abortion without a
medical reason is legal, it’s certainly hard to argue against it when there is
a medical reason.But as our
potential information increases – as we learn more about how various mutations
can affect a person’s phenotype – these issues will arise in more and more
cases, many in much grayer areas than those discussed above.

What about mutations causing
conditions like autism, for example, maybe only in a percentage of people who
inherit them?Is that information
prospective parents would want or would act on?There is a question of personal choice there, but also
whether society wants that choice (i.e., one based on genetic information) to
be available.Should screening for
sex be allowed?This is a
different proposition when selecting embryos in vitro than in prenatal testing
and selective termination of a fetus based on sex.The latter has been common in China and India for years and
has resulted in a massively skewed sex ratio in some areas.The United Nations Population Fund concluded that “if the continent’s overall sex ratio
was the same as elsewhere in the world, in 2005 Asia’s population would have
included almost 163 million more women and girls.”

These are just some of the possible
ramifications of increased access to genetic information that society will have
to figure out how to deal with.One final note: in the film, our hero overcomes his genetic destiny,
proving the predictions wrong in his case. That is a timely reminder to remember both the limits of our current
knowledge and also the more fundamental limits of phenotypic prediction based
on genetic data.The fact that
monozygotic (“identical”) twins are really not identical for many traits (or in
affected status for many disorders) shows directly the limits of genetic
determinism and reinforces the fact that the individuality of each person goes far beyond their genome.